HLA-C⁣∗0304 Associates With Beneficial Gut Microbiota and Later Onset of Type 1 Diabetes in Pediatric Cohorts

TL;DR

This study shows that the HLA-C*0304 gene variant is linked to a healthier gut microbiome and later onset of type 1 diabetes in children.

Contribution

The study identifies HLA-C*0304 as a novel genetic factor associated with beneficial gut microbiota and delayed T1DM onset.

Findings

HLA-C*0304 carriers had delayed T1DM onset compared to noncarriers.

HLA-C*0304-positive T1DM patients had higher levels of beneficial gut bacteria like Blautia and Lachnospiraceae.

High-HLA-risk T1DM patients showed distinct gut microbiota differences from controls.

Abstract

To investigate whether human leukocyte antigens (HLAs) influence gut microbiota composition and contributes to delayed type 1 diabetes mellitus (T1DM) onset in children.

This multicenter cross-sectional study included 106 newly diagnosed pediatric T1DM patients (age <18 years) and 69 healthy controls from nine Chinese cities. Gut microbiota was profiled via whole-metagenome shotgun sequencing, and HLA alleles were genotyped by PCR sequence-based typing. Participants were stratified by HLA-risk scores. Statistical analyses included α/β-diversity metrics, linear discriminant analysis effect size analysis (LEfSe), and Spearman correlation adjusted for confounders.

Principal coordinates analysis (PCoA) exposed discernible disparities in gut microbiota structures within the high-HLA-risk T1DM cohort relative to both high- and low-HLA-risk control groups (R2 = 0.0562, p=0.003 and R2 = 0.0343, p=0.003). HLA-C∗0304 carriers exhibited delayed T1DM onset compared to noncarriers (adjusted R2 = 0.225, p=0.017). High-HLA-risk T1DM patients showed distinct microbiota divergence from controls (R2 = 0.0562, p=0.003), driven by reduced Lachnospiraceae and Blautia (butyrate producers) in noncarriers. Conversely, HLA-C∗0304-positive T1DM patients had enriched Blautia (p=0.005) and Lachnospiraceae (p=0.039), alongside lower opportunistic pathogens (Citrobacter; p < 0.05). High-HLA-risk patients also displayed lower fasting C-peptide levels than low-risk counterparts (0.19 ± 0.14 vs. 0.26 ± 0.19 µg/mL, p=0.029).

Our study demonstrates that specific HLA class I subtypes (e.g., C∗0304) may modulate T1DM onset through selective enrichment of beneficial gut microbiota. Elucidating the mechanisms by which HLA variants regulate mucosal immunity and coordinate HLA-microbiota-immune interactions holds significant potential for developing targeted interventions against T1DM pathogenesis.

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